JP2009061343A - Loss prevention method of active ingredient of radiopharmaceutical in prefilled syringe - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a loss prevention method of active gradients of radiopharmaceutical in prefilled syringes capable of applying a high sealing property preventing the liquid leakage even if being disposed with a gasket by a vacuum plugging method, improving the sliding property between the gasket and a syringe and preventing the adhesion of the radiopharmaceutical to the gasket. <P>SOLUTION: The gasket 11 has such a shape as having two or more annular projection portions 13a, 13b and 13c which continuously and circumferentially project to the outer circumferential face in contact with the inner circumferential face of the syringe. A medicine contact face 17 of the gasket and a molding formed in the medicine contact face side and including at least one annular projection portion 13a are formed of fluororubber molding 15 molded by including fluororubber. When manufacturing prefilled syringes, this constitution can prevent the adhesion (including the adsorption) of the radiopharmaceutical to the gasket in the storage and in use and secure the high sealing property of the prefilled syringe. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  TECHNICAL FIELD The present invention relates to a prefilled syringe filled with a medicine in advance, and a gasket disposed inside the syringe of the medicine filled, and in particular, the medicine is a radiopharmaceutical. The present invention relates to a method for preventing loss of an active ingredient of a radiopharmaceutical in a syringe filled with a liquid medicine.

  As a container for a radiopharmaceutical, a syringe filled with a liquid medicine in which a syringe prefilled with a radiopharmaceutical is sealed is generally used. In this syringe filled with a liquid medicine, the medicine inside the syringe barrel is sealed. In addition, a gasket formed of a rubber elastic body such as a synthetic rubber or a thermoplastic elastomer is usually disposed inside the syringe barrel.

  Conventionally, in a gasket used in such a syringe filled with a chemical solution, in order to prevent a compounding agent contained in rubber, for example, sulfur, a vulcanization accelerator, etc. from leaching into a pharmaceutical product during storage, In order to prevent the contained preservative or medicine itself from adsorbing to the gasket, a technique of partially coating or laminating a fluorine resin thin film on the medicine contact portion of the gasket is known (see Patent Document 1). .

  In addition, since the lubricant applied to the gasket and the inner wall of the syringe barrel is mixed into the drug as foreign matter and fine particles, and adverse effects on the human body have been regarded as a problem, preventing the mixing of foreign matter and fine particles into the pharmaceutical product, and In order to improve the slidability between the gasket and the syringe barrel, the entire surface of the sliding portion of the gasket between the drug contact portion and the inner peripheral surface of the syringe barrel is made of a tetrafluoroethylene resin film having a thickness of 0.01 to 0.1 mm. A technique for stacking has been proposed (see Patent Document 2).

  Furthermore, in order to obtain a gasket that has sufficient liquid and air tightness during storage, and that has good slidability during use, there is no risk of contamination or elution of pharmaceutical products. A technique for coating a thin plastic film is proposed (see Patent Document 3).

  FIG. 6 is a cross-sectional view showing the above-described syringe filled with a liquid medicine. The syringe 52 that has been filled with a chemical solution is usually a transparent glass syringe 56 filled with a radiopharmaceutical (injection solution) 54, a rubber plug 58 inserted into the tip of the syringe 56, A rubber gasket 60 inserted into the rear end portion and an injection needle mounting portion 62 attached to the distal end of the syringe barrel 56 and fitted on the needle base 74 of the injection needle 72 on the distal end side are provided. The injection solution 54 is filled in between 60 and 60.

In the above-described syringe filled with the liquid medicine, when the injection liquid 54 is filled into the injection cylinder 56, the injection liquid 54 is filled into the injection cylinder 56 into which the rubber stopper 58 is inserted, and then the gasket 60 is inserted into the injection cylinder. Place inside 56 and seal. When sealing the inside of the syringe barrel 56, in order to remove the gas existing between the rubber stopper 58 and the gasket 60, the gasket 60 is usually arranged inside the syringe barrel 56 in the following manner.
(1) The injection solution 54 is filled into the syringe barrel 56 in which the rubber plug 58 is inserted.
(2) A thin hollow needle (or wire) having hardness is inserted into the syringe barrel 56 from the rear end opening so that the hollow needle contacts the inner peripheral surface of the syringe barrel 56 at a position where it does not contact the injection solution 54. To place.
(3) The gasket 60 is inserted into the syringe barrel 56 and the hollow needle is sandwiched between the gasket 60 and the inner peripheral surface of the syringe barrel 56 so that the upper and lower spaces of the gasket 60 are communicated by the hollow needle. .
(4) The syringe barrel 56 in the state of (3) is put in a decompressor, and the inside of the decompressor is decompressed. When the gasket 60 is pushed to just above the injection solution 54, the hollow needle is removed from the inside of the injection tube 56, and then the atmospheric pressure in the decompressor is returned to normal pressure.

  The injection solution 54 is sealed inside the syringe barrel 56 by removing a certain amount or more of the gas existing between the rubber plug 58 and the gasket 60 by the above-described method, that is, a so-called vacuum plugging method.

  However, in the conventional gasket, as described above, a fluororesin thin film is coated or laminated on the pharmaceutical contact portion of the gasket 60 and the sliding portion with the syringe 56, or the surface of the gasket 60 is made of plastic. When the hollow needle is sandwiched between the gasket 60 and the inner peripheral surface of the syringe barrel 56 as described in (3) above, the gasket 60 is coated or laminated. The thin film portion is deformed due to wrinkles. In many cases, the deformed portion is not restored in shape even after the hollow needle is removed, and in the deformed portion, a gap is formed between the gasket 60 and the inner peripheral surface of the syringe barrel 56, There is a problem that the injection solution 54 filled in the syringe barrel 56 leaks to the outside through this gap.

  Among the pharmaceuticals, particularly, radiopharmaceuticals have a property that radionuclides are likely to adhere (including adsorption) to the pharmaceutical contact portion of the gasket 60, and the nuclide adhering to the gasket 60 in this way is physiological saline, hydrochloric acid. Even if it is washed with an aqueous solvent such as a non-aqueous solvent such as diethyl ether, it is difficult to completely wash it out. In addition, in the case of radiopharmaceuticals, the concentration is usually very low, so the amount of radionuclide attached sometimes exceeds 20% of the amount of radioactivity charged, so it is necessary to attach it for accurate radioactivity administration. As a result, it was necessary to make up for the loss, and as a result, the radioactivity content had to be increased. On the other hand, disposal of used gaskets with attached radionuclides and related exposure problems also occurred, and it was necessary to take special measures for worker exposure management.

Japanese Utility Model Publication No. 52-19435 Japanese Patent Publication No. 7-47045 Japanese Patent No. 3211223

  In view of the above-described problems, the present invention can provide high sealing performance that does not cause liquid leakage even when a gasket is arranged using a vacuum plugging method. It is an object of the present invention to provide a method for preventing loss of an active ingredient of a radiopharmaceutical in a syringe filled with a liquid that can improve the mobility and prevent the radiopharmaceutical from adhering to a gasket.

  As a result of earnest research to solve such problems, the present inventor has found that in a syringe filled with a radiopharmaceutical in advance, the gasket disposed inside the syringe barrel is made of fluororubber. It has been found that by having a fluororubber molded body that is contained and molded, the sealing performance is improved while retaining high slidability, and the radiopharmaceutical can be prevented from adhering to the gasket, and the present invention is completed. It came to.

  That is, according to the present invention, when a gasket is placed in contact with the inner peripheral surface of a syringe barrel in a syringe filled with a liquid medicine in advance, the gasket is brought into contact with the inner peripheral surface of the syringe barrel. Fluorine is formed into a shape having two or more annular protrusions protruding in the circumferential direction continuously on the outer peripheral surface, and including at least one annular protrusion formed on the drug contact surface and the drug contact surface side of the gasket. By forming a fluororubber molded product containing rubber, it prevents the attachment (including adsorption) of radiopharmaceuticals to the gasket during manufacture, storage and use of a syringe filled with a chemical solution, and a chemical solution Provided is a method for preventing loss of an active ingredient of a radiopharmaceutical in a syringe filled with a chemical solution, which ensures high sealing performance in the filled syringe.

  According to the present invention, it is possible to provide a high sealing property that does not leak even if a gasket is arranged using a vacuum plugging method, and to improve the sliding property between the gasket and the syringe barrel. In addition, it is possible to provide a method for preventing the loss of the active ingredient of the radiopharmaceutical in the syringe filled with the liquid medicine that can prevent the radiopharmaceutical from adhering to the gasket.

  Next, embodiments of the present invention will be described with reference to the drawings, but the present invention is not limited to the following examples.

(First embodiment)
FIG. 1 is a cross-sectional view showing an embodiment of a syringe filled with a chemical solution according to the present invention, and FIG. 2 is an enlarged cross-sectional view of the gasket in FIG. As shown in FIG. 1 and FIG. 2, the syringe 1 filled with the liquid medicine of this example includes an injection cylinder 3 made of hard glass, a rubber stopper (blocking member) 7 inserted into the distal end portion of the injection cylinder 3, and an injection cylinder 3 is provided with a gasket 11 arranged on the rear end side of the inside of the syringe 3 and an injection needle mounting portion 5 attached to the tip of the syringe barrel 3, and a radiopharmaceutical (injection solution) 9 is filled inside the syringe barrel 3. The injection solution 9 is sealed between the rubber stopper 7 and the gasket 11.

  The gasket 11 has three annular protrusions 13a, 13b, and 13c that continuously protrude in the circumferential direction on the outer peripheral surface that comes into contact with the inner peripheral surface of the syringe barrel 3 of the syringe 1 that has been filled with the liquid medicine. It consists of a fluororubber molding 15 that is contained and molded. Therefore, the portion including the pharmaceutical contact surface 17 and the three annular convex portions 13a, 13b, 13c is formed of the fluororubber molded body 15. In addition, the gasket 11 is provided with a hollow portion 19 to which the distal end portion of the plunger 21 can be attached.

  When administering the injection solution 9 inside the syringe barrel 3, the plunger 21 is attached to the hollow portion 19 of the gasket 11, and then the syringe needle (double-edged needle) is attached to the syringe needle attachment portion 5 provided at the tip of the syringe barrel 3. And the rubber plug 7 is pierced with an injection needle. Thereafter, the gasket 11 can be slid by pushing the plunger 21.

(Second embodiment)
FIG. 3 is a side view showing an embodiment of the gasket according to the present invention, and FIG. 4 is a sectional view of the gasket taken along the line AA of FIG. As shown in FIGS. 3 and 4, the gasket 31 of this example has three annular protrusions 33 a that continuously protrude in the circumferential direction on the outer peripheral surface that comes into contact with the inner peripheral surface of the syringe barrel of the syringe filled with the liquid medicine. A fluororubber molded body 35 having 33b and 33c and molded by containing fluororubber and a butyl rubber molded body 37 molded by containing butyl rubber are joined. In this example, the molded product including the pharmaceutical contact surface 39 of the gasket and the one annular convex portion 33 a formed on the pharmaceutical contact surface side is formed of the fluororubber molded product 35. The gasket 31 is provided with a hollow portion 41 to which the distal end portion of the plunger 21 can be attached.

  Hereinafter, the syringe and gasket filled with the chemical solution according to the present invention will be further described. The syringe filled with the drug solution in the present invention is usually a syringe made of hard glass, amorphous polyolefin, polyethylene resin, etc., and the radiopharmaceutical inside the syringe barrel inserted into the tip of the syringe barrel in a liquid-tight manner. A closing member for closing, a gasket disposed at a rear end portion inside the syringe barrel, and an injection needle mounting portion attached to the tip of the syringe barrel are provided. When administering the injection solution, the needle base of the injection needle (double-edged needle) is mounted on the injection needle mounting portion, and the blocking member is pierced and penetrated by the injection needle. The closing member is usually formed of a rubber-like elastic body.

  The gasket disposed in the syringe filled with the drug solution according to the present invention may be any gasket as long as it has two or more annular convex portions protruding in the circumferential direction continuously to the outer peripheral surface contacting the inner peripheral surface of the syringe barrel. For example, the annular convex portion has a thickness (axial thickness) that decreases from the inner circumferential direction toward the outer circumferential direction, a thickness that increases from the inner circumferential direction toward the outer circumferential direction, Those having the same thickness from the inner peripheral direction toward the outer peripheral direction, those having an edge or an obtuse angle at the edge of the annular convex portion, or those having a roundness can be used. The gasket is continuous in the circumferential direction from the outer peripheral surface in contact with the inner peripheral surface of the syringe barrel from the viewpoint of ensuring the sealing performance inside the syringe barrel and stable slidability during administration of the injection solution and preventing knocking. It has two or more projecting annular projections, usually has three annular projections, and the thickness of the annular projections decreases from the inner circumferential direction to the outer circumferential direction, and the edge of the annular projections What has a round part is preferable.

  The gasket according to the present invention is a molded product including a pharmaceutical contact surface and at least one annular projection formed on the pharmaceutical contact surface side, which is formed of a fluoro rubber molded product. Or a gasket in which a fluororubber molded body and a rubber-like elastic molded body molded by containing a rubber-like elastic body other than fluororubber are joined. It is possible to use a gasket formed by joining two molded bodies with a cylindrical elastic molded body, a gasket formed by bonding three molded bodies of a fluoro rubber molded body and 2 rubber-like elastic molded bodies, or the like.

  Furthermore, in the gasket according to the present invention, for example, in a gasket formed by joining two molded bodies of a fluororubber molded body and a rubber-like elastic molded body, one annular formed on the drug contact surface and the drug contact surface side. A molded body including a convex portion is formed of a fluororubber molded body, and a molded body including a pharmaceutical contact surface and two annular convex portions formed on the pharmaceutical contact surface side is formed of a fluororubber molded body. Can be used.

  In the present invention, since the pharmaceutical contact surface of the gasket is formed of a fluororubber molding, the radionuclide of the radiopharmaceutical can be prevented from adhering to the pharmaceutical contact surface of the gasket. For example, if the pharmaceutical contact surface of the gasket is molded using butyl rubber or silicone rubber instead of a fluoro rubber molding, the radionuclide of the radiopharmaceutical and the main carrier are attached to the pharmaceutical contact surface of the gasket. This is not preferable.

  Moreover, when the gasket is placed inside the syringe barrel, a vacuum plugging method is provided because the molded body including at least one annular projection formed on the pharmaceutical contact surface side of the gasket is formed of a fluororubber molded body. Even if is used, high sealing performance can be ensured without liquid leakage. That is, when vacuuming is performed, the hollow needle is removed even if the hollow needle (or the wire) is sandwiched between the gasket and the inner peripheral surface of the syringe barrel and the gasket is wrinkled. Since the deformed shape is restored to the original shape, no gap is formed between the gasket and the inner peripheral surface of the syringe barrel.

  When the molded body including at least one annular projection formed on the pharmaceutical contact surface side of the gasket is not formed of a fluororubber molding, for example, a thin film such as a fluororesin is coated or laminated on the annular projection of the gasket. If a vacuum punching is performed, when a hollow needle is sandwiched between the gasket and the inner peripheral surface of the syringe barrel, wrinkles may occur in the gasket coating or laminated thin film portion. Shape deformation occurs, the deformed shape is not restored after removing the hollow needle, a gap is formed between the gasket and the inner peripheral surface of the syringe barrel, and the injection solution filled in the syringe barrel from the gap is externally It cannot be secured because of leakage.

  In the present invention, the fluororubber contained in the fluororubber molding of the gasket is, for example, a fluorine compound selected from vinylidene fluoride, hexafluoropropylene, tetrafluoroethylene, perfluoromethyl vinyl ether, and polyvinyl difluoride. A copolymer containing one or more kinds can be given, and propylene and ethylene can be included. Among them, the fluororubber is preferably a copolymer containing one or more fluorine compounds selected from vinylidene fluoride, propylene hexafluoride, and ethylene tetrafluoride, for example, a copolymer of ethylene tetrafluoride and propylene, Copolymer of polyvinyl difluoride and propylene hexafluoride, Copolymer of polyvinyl difluoride, hexafluoropropylene and tetrafluoroethylene, Copolymer of tetrafluoroethylene, propylene and polyvinyl difluoride A coalescence or the like can be used.

  The fluororubber contained in the fluororubber molded product usually contains 55% by weight or more of fluorine, preferably 60 to 65% by weight of fluorine in terms of preventing the attachment of radionuclides of radiopharmaceuticals. Can be used.

  Further, the fluororubber can be crosslinked by methods such as polyol vulcanization, peroxide vulcanization, radiation vulcanization, electron beam vulcanization, and plasma vulcanization. By crosslinking by these methods, it is possible to prevent by-products and the like from being contained in the fluororubber, so that the rubber elastic body used in radiopharmaceuticals is in a good state, that is, carbon disulfide, secondary amine, and other by-products. Inclusion can be reduced, and even when fluororubber comes into contact with a radiopharmaceutical, by-products and the like can be prevented from eluting into the radiopharmaceutical and causing a chemical change. In particular, peroxide vulcanization is particularly suitable for gaskets of prefilled syringes filled with a radiopharmaceutical because it has a particularly small amount of eluate from the drug and is excellent in chemical resistance and steam resistance.

  In addition, the said fluoro rubber can use the thing of the range whose international rubber hardness defined by the specification by JIS-K6253 is 40-70IRHD, especially the range of 55-60IRHD. If the international rubber hardness is less than 40 IRHD, liquid may leak from the contact portion of the gasket with the inner peripheral surface of the syringe barrel when a drug is administered from a syringe filled with a chemical by applying pressure to the gasket. This is not preferable because the sealing performance cannot be secured. Also, if the international rubber hardness is greater than 70 IRHD, the sliding resistance of the gasket will increase, and it may become difficult to administer the drug from a syringe filled with a chemical solution, or with a decompressor when performing vacuum capping. There is a possibility that the gasket cannot be pushed in just above the medicine and cannot be plugged, and because the gasket is inflexible, when a hollow needle is sandwiched between the syringe barrel and the gasket in a vacuum stopper In addition, the deformed gasket is difficult to return to its original shape, and a gap is formed between the gasket and the inner peripheral surface of the syringe barrel, which may cause the medicine filled in the syringe barrel to leak to the outside. It is not preferable because the property cannot be secured.

  In addition, the fluororubber molded article contains at least one additive selected from reinforcing agents, coloring pigments, processing aids, acid acceptors, cross-linking agents, cross-linking aids, and the like as long as the object of the present invention is not impaired. It can be contained as appropriate. For example, silica, carbon black, clay, barium sulfate, precipitated barium sulfate, talc, calcium silicate, etc. as reinforcing agents, titanium oxide, carbon black, etc. as coloring pigments, stearic acid, stearylamine, octadecyl as processing aids Amine, sodium stearate, etc., magnesium hydroxide, calcium hydroxide, etc. as acid acceptor, polyamine, polyol, peroxide etc. as crosslinking agent, triallyl isocyanurate, trimethallyl cyanurate, triamine as crosslinking aid Examples include allyl trimellitate, 1,3-butylene dimethacrylate, 1,6-hexanediol methacrylate, and polyethylene glycol dimethacrylate. Moreover, in order to improve the flexibility, the fluororubber molded body can be blended with a fluorine oil made of a copolymer such as vinylidene fluoride and hexafluoropropylene.

  In the gasket according to the present invention, the rubber-like elastic molded body molded by containing a rubber-like elastic body other than fluoro rubber is, for example, one or more rubber-like elastic bodies selected from the group consisting of synthetic rubber and thermoplastic elastomer. Can be molded. Synthetic rubbers include butyl rubber, chlorinated butyl rubber, brominated butyl rubber, divinylbenzene partially crosslinked rubber, brominated isobutylene-paramethylstyrene copolymer rubber, isoprene rubber, butadiene rubber, ethylene propylene rubber, ethylene propylene terpolymer, styrene-butadiene rubber Nitrile rubber, chloroprene rubber, silicone rubber, urethane rubber, and the like. Examples of the thermoplastic elastomer include styrene-based, polyester-based, olefin-based, and fluorine-based thermoplastic elastomers. Chlorinated butyl rubber molding that contains butyl rubber as the main component in terms of its excellent sealing and sliding properties as a rubber-like elastic molding that contains a rubber-like elastic body other than fluoro rubber. The body is preferred.

  As a method for producing a gasket used for a syringe filled with a chemical solution in the present invention, a gasket made only of a fluororubber molding can be molded by a general method using a molding die.

Further, a gasket formed by bonding a fluororubber molded body and a rubber-like elastic molded body molded by containing a rubber-like elastic body other than fluororubber can be manufactured by the procedure shown in FIG. 5, for example. .
(1) A fluororubber unvulcanized sheet 81 is placed on a primary molding die 80.
(2) The fluororubber unvulcanized sheet 81 is pressed from above and crosslinked by applying temperature.
(3) The fluororubber molded body 82 is molded and punched to a desired size.
(4) Put the fluororubber molded body 82 in a main molding (secondary molding) mold 83 and apply an adhesive 84 on the upper surface.
(5) A rubber-like elastic sheet 85 other than fluororubber such as a primary vulcanized butyl rubber sheet is placed on the mold 83 for molding.
(6) The rubber-like elastic body sheet 85 is pressed from above and is cross-linked by applying a temperature to join the fluororubber molded body 82 and the butyl rubber molded body 86 together.
(7) A gasket 87 is formed by punching out a joined body of the fluororubber molded body 82 and the butyl rubber molded body 86.

  Further, regarding a gasket formed by joining a fluororubber molding and a rubber-like elastic molding containing a rubber-like elastic body other than fluororubber, the fluororubber molding and a rubber-like elasticity other than fluororubber The rubber-like elastic molded body that contains the body and is molded individually with a molding die, and these molded bodies may be joined with an adhesive or the like.

  As the radiopharmaceutical prefilled inside the syringe barrel of the syringe filled with the medical solution in the present invention, a medicament having one or more radionuclides selected from iodine 123, iodine 131, thallium 201 and fluorine 18 is particularly preferably used. Can do.

[Example 1]
(Create gasket)
Unvulcanized fluoro rubber (copolymer of vinylidene fluoride and propylene hexafluoride) kneaded together with additives such as crosslinking aids and primary vulcanized into a sheet (fluoro rubber unvulcanized sheet) as a gasket It was placed in a molding die and vulcanized by a peroxide vulcanization method to form a gasket made of a fluororubber molding. The obtained gasket has a cylindrical shape having three annular protrusions, the diameter of the maximum outer periphery of the annular protrusion is 9.2 mm, and a hollow portion is provided to which the tip of the plunger can be attached. It was.
(Preparation of pre-filled syringe)
A radiopharmaceutical 2 mL (I-123) containing iodine 123 (I-123) in a syringe barrel (inner diameter: 8.6 mm) in which a certain amount of silicone is applied to the inner peripheral surface and the inside of the tip portion is closed with a rubber stopper ( (Concentration: 74 MBq / mL, amount of radioactivity: 148 MBq), and the radiopharmaceutical was sealed by a vacuum plugging method using the gasket obtained above. The filling of the radiopharmaceutical and the vacuum plugging were performed at a temperature of 25 ° C., and a hollow needle was used for the vacuum plugging.

[Example 2]
A fluororubber unvulcanized sheet similar to that in Example 1 is placed in a gasket primary molding die, vulcanized by the peroxide vulcanization method, molded, and one annular ring on the pharmaceutical contact surface and pharmaceutical contact surface side of the gasket. A molded body including the convex portion was formed of a fluororubber molded body. Next, apply the adhesive to the joint surface with the chlorinated butyl rubber molded body and place it in the secondary molding die, and place the chlorinated butyl rubber sheet on it and mold it. A gasket formed by joining a fluororubber molding and a chlorinated butyl rubber molding was formed. The shape and size of the obtained gasket were the same as those of the gasket of Example 1. In the same manner as in Example 1, the radiopharmaceutical was sealed by the vacuum stopper method using the gasket obtained above.

[Comparative Examples 1-5]
As a comparative example, the following gaskets having the same shape and size as those in Example 1 were prepared, and radiopharmaceuticals were sealed by vacuum punching using these gaskets in the same manner as in Example 1.
Comparative Example 1: Gasket made of chlorinated butyl rubber (generally used for a syringe filled with a chemical solution).
Comparative Example 2: A gasket made of silicone rubber.
Comparative Example 3: A gasket obtained by laminating polytetrafluoroethylene (PTFE) having a thickness of 50 μm on the pharmaceutical contact surface of a gasket made of chlorinated butyl rubber and the surfaces of three all-annular convex portions.
Comparative Example 4: A gasket made by laminating PTFE having a thickness of 80 μm on the surface of the pharmaceutical contact surface of the gasket made of chlorinated butyl rubber and the first annular convex portion on the pharmaceutical contact surface side.
Comparative Example 5: Gasket made by laminating PTFE having a thickness of 50 μm on the surface of the pharmaceutical contact surface of the gasket made of chlorinated butyl rubber and the first annular convex portion on the pharmaceutical contact surface side.

[Evaluation of syringe filled with chemical solution]
The following evaluations were performed on the drug solution-filled syringes in Examples 1 and 2 and Comparative Examples 1 to 5.
(Evaluation on sealing performance)
For the syringes filled with the chemical solution in Examples 1 and 2 and Comparative Examples 1 to 5, after the gasket was plugged by the vacuum punching method, the first annular convex portion on the pharmaceutical contact surface side of the gasket was changed to the second annular convex portion. The occurrence of liquid bleeding (so-called liquid rising) in the meantime was visually confirmed. The results are shown in Table 1.
(Evaluation for adsorption)
About the syringe with which the chemical | medical solution filling in Example 1 and 2 and Comparative Examples 1-5 was filled for 24 hours in the environment of 25 degreeC and 50 degreeC, respectively, after injecting the radiopharmaceutical inside a syringe barrel, the amount of radioactivity was measured. . In this case, the radioactivity concentration in the chemical solution injected from the syringe filled with the chemical solution was converted into the radioactivity concentration per unit volume, and the adsorption rate was determined. Specifically, the adsorption rate of iodine-123 with respect to the gasket was calculated by the following equation. The results are shown in Table 1.
A = {(BC) / B} × 100
A: Adsorption rate of iodine-123 (%)
B: Radioactive concentration of radiopharmaceutical before filling syringe (MBq / mL)
C: Radiopharmaceutical radioactivity concentration (MBq / mL) after storage for 24 hours
(Evaluation on slidability)
About the syringe filled with the chemical solution in Examples 1 and 2 and Comparative Examples 1 to 5, a plunger is attached to the hollow portion of each gasket, and a double-edged needle is attached to the injection needle attachment portion provided in each syringe barrel. The rubber plug that had been pierced was penetrated. Next, the force applied to the gasket was measured by sliding the gasket by pushing the plunger at a constant speed, and the maximum force required when the gasket started moving was taken as the measured value. Table 1 shows the results of the measured values when the measured value when the gasket (Comparative Example 1) made of chlorinated butyl rubber used for a general drug solution-filled syringe is slid is 1.0.
(Eluate test)
About each gasket used with the syringe filled with the chemical | medical solution in Examples 1 and 2 and Comparative Examples 1-5, the eluate test was implemented by the 14th revision Japanese Pharmacopoeia infusion rubber plug test method. The results are shown in Table 2.

  As can be seen from the results of the evaluation of sealing performance in Table 1, in the syringe filled with the liquid medicine according to the present invention, when the gasket is stoppered by the vacuum stopper method, the liquid of the radiopharmaceutical to the peripheral portion of the annular convex portion of the gasket It was confirmed that no rise was observed and the sealing performance was secured. On the other hand, in the syringe filled with the chemical solution using the gasket laminated with PTFE (Comparative Examples 3 to 5), when the gasket is stoppered by the vacuum stopper method, the first annular convex portion on the pharmaceutical contact surface side To the second annular convex portion, liquid rising occurred, and hermeticity could not be secured.

  In addition, as can be seen from the results of the adsorption evaluation in Table 1, the radionuclide adsorbed on the gasket was observed in the case of the pre-filled syringe according to the present invention when stored at a room temperature of 25 ° C and a high temperature of 50 ° C. There wasn't. On the other hand, in the syringe filled with the chemical solution using the gasket made of chlorinated butyl rubber and the gasket made of silicone rubber (Comparative Examples 1 and 2), both cases were stored at room temperature of 25 ° C. and high temperature of 50 ° C. Adsorption of radionuclide to the gasket is observed, especially when stored at a high temperature of 50 ° C., 20% of the gasket made of chlorinated butyl rubber and 27% of the gasket made of silicone rubber are generated. It was found that not only the amount of radioactivity required at the time of administration could not be ensured, but also the quality standards shown in the radiopharmaceutical standards and the quality standards at the time of manufacture were not met.

  Moreover, as can be seen from the results of the slidability evaluation in Table 1, the drug solution-filled syringe according to the present invention has a value close to that of a gasket (Comparative Example 1) made of chlorinated butyl rubber used for a general drug solution-filled syringe. Since it was shown, it was judged that the injection solution could be administered. On the other hand, the drug solution-filled syringe using the gasket made of silicone rubber and the gasket laminated with PTFE (Comparative Examples 2 to 5) showed a high value of 2.5 to 3.0. It not only made the person feel uncomfortable, but also required a strong force, which made it difficult to administer the injection solution and was difficult to use.

  Further, as can be seen from the results in Table 2, it was confirmed that the gasket used in the syringe filled with the drug solution according to the present invention conforms to the standards for the elution test of the rubber stopper test method for infusion.

  From the above results, the syringe filled with the liquid medicine according to the present invention has a high sealing property that does not leak even when the gasket is plugged using the vacuum plugging method, and is excellent in the slidability of the gasket, And it turned out that it can prevent that a radiopharmaceutical adheres to a gasket.

It is sectional drawing which shows one Embodiment of the syringe filled with the chemical | medical solution used for this invention. It is sectional drawing to which the gasket in FIG. 1 was expanded. It is a side view which shows one Embodiment of the gasket used for this invention. It is sectional drawing in the AA of the gasket of FIG. It is the schematic which shows the manufacturing method of the gasket used for this invention. It is sectional drawing which shows the pre-filled syringe and the injection needle (double-edged needle) of a radiopharmaceutical.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Syringe filled with chemical | medical solution 3 Injection cylinder 5 Injection needle mounting part 7 Rubber stopper (occlusive member)
9 Radiopharmaceuticals (injection solution)
11 Gasket 13a, 13b, 13c Annular convex part
15 Fluoro rubber molding 17 Pharmaceutical contact surface 19 Hollow part 21 Plunger 31 Gaskets 33a, 33b, 33c Annular convex part
35 Fluoro rubber molded body 37 Butyl rubber molded body 39 Pharmaceutical contact surface 41 Hollow portion 80 Primary molding die 81 Fluoro rubber unvulcanized sheet 82 Fluoro rubber molded body 83 Secondary molding die 84 Adhesive 85 Rubber elastic body sheet 86 Butyl rubber molding 87 Gasket

Claims (6)

  When placing a gasket in contact with the inner peripheral surface of a syringe barrel in a syringe filled with a liquid medicine in advance and filled with a radiopharmaceutical in advance, the gasket is continuously connected to the outer peripheral surface in contact with the inner peripheral surface of the syringe barrel. Forming a shape having two or more annular protrusions protruding in the circumferential direction and including a fluororubber containing a molded product including the pharmaceutical contact surface of the gasket and at least one annular protrusion formed on the pharmaceutical contact surface side By forming it with a molded fluororubber, it prevents radiopharmaceuticals from adhering to the gasket (including adsorption) during manufacturing, storage and use of the drug-filled syringe, and at the same time seals high in a drug-filled syringe A method for preventing loss of an active ingredient of a radiopharmaceutical in a syringe prefilled with a liquid solution, which is characterized by ensuring the property.   The gasket is characterized in that a fluororubber molded body molded containing fluororubber and a rubber-like elastic molded body molded containing a rubbery elastic body other than fluororubber are joined. Item 2. A method for preventing loss of an active ingredient of a radiopharmaceutical in a syringe filled with a chemical solution according to Item 1.   3. The radiopharmaceutical in a syringe filled with a drug solution according to claim 2, wherein the rubber-like elastic body other than fluororubber is an elastic body containing at least one selected from synthetic rubber and thermoplastic elastomer. To prevent loss of active ingredients.   The radiopharmaceutical is a pharmaceutical having at least one radionuclide selected from iodine 123, iodine 131, thallium 201 and fluorine 18, and filled with a chemical solution according to any one of claims 1 to 3 Method for preventing loss of active ingredient of radiopharmaceutical in syringe.   The fluororubber contained in the fluororubber molded article contains 55% by weight or more of fluorine, wherein the active ingredient of the radiopharmaceutical in the syringe filled with the drug solution according to any one of claims 1 to 4, Loss prevention method.   The method for preventing loss of an active ingredient of a radiopharmaceutical in a syringe filled with a drug solution according to any one of claims 1 to 5, wherein the fluororubber contained in the molded fluororubber has an international rubber hardness of 40 to 70 IRHD. .

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